Solvation and Weak Interactions“Like dissolves like”: appropriate, but not sufficient.So, specific (often weak) intermolecular interactions responsible for solubility.Depends on relative magnitudes of KAA, KBB, KABGains:SAentropy of molecular dispersionKABweak interactions between A, BLosses:SBsolvent B is ordered around AKAAbroken interactions between A-AKBBsame for B-BSolvation and Weak InteractionsClClClC60solubility in:20 mg/mL1.8 mg/mL0.037 mg/mLONot just “like dissolves like”;Specific solvent-solute interactions responsible for solubility differences.High oxidation potential of C60(E0= 0.44 V) means electrons easily donated to electron poor partners (like trichlorobenzene).Solvent Scales(from MPOC text, page 147)Dielectric constant (ε):Measure of polarity, polarizabilityValues obtained by measuring capacitance across solventTaft α/β:Measure of proton donating/proton accepting characterInteresting contrast:Acetic acid & ethyl acetateSame dielectric constant, but very different miscibility with water(AcOH infinitely miscible,EtOAc immiscible)Solvent ScalesGutmann acceptor/donor numbers (AN/DN): measure of Lewis basicity/acidity.solvent acceptor number (AN)donor number (DN)H2O 54.8 18MeOH 41.3 19.1EtOH 37.1 19.21-Propanol 37.7 19.82-Propanol 33.8 21.1t-Butanol 27.1 21.9DMSO 19.3 29.8MeCN 18.9 14.1Nitromethane 20.5 2.7Diethyl ether 3.9 19.2CCl48.6 0Benzene 8.2 0Hexane 0 0H3CSCH3ODMSO: Great e-donor, but poor acceptorH3COHMethanol: Good e-donor, but great e-acceptor (H-donor)Point is not importance of this particular scale, but rather differences in the ways scales are defined, how solvents and solutes interact.Weak Interactions• Earlier, discussed strong bonding interactions, BDEs ≈ 50-200 kcal/mol.• Structures, properties, activities of molecules also depend on weaker, non-bonding interactions. (As does solvent character.)• Biological molecules, polymer materials, organic molecule/drug design, analyte recognition, all depend on weak interactions.• But…they are much harder to measure and characterize.Hydrogen BondingWhat you probably already know:H3C CH3OHORCo-linear arrangement is preferred;Orbital overlap optimized when Osp2is directed at O-H σ*.H3C CH3OHOROsp2O-H σ*• Other angles about oxygen > 120°are well accommodated (H-bond almost as strong)*• Other angles about hydrogen are poorly accommodated (weaker H-bond)*(*see e.g. Morozov, A. V. et al. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 6946.)Hydrogen BondingWhat you may not know:“Strength” of H-bond depends on context.BDEs are measured without context:R1—R2→ R1+ R2ΔHr= BDETypically measured in the gas phase (vacuum):BDE (H2O•HF) = 8 kcal/molBDE (CH3OH•HCl) = 7 kcal/mol(Geometries from gas-phase spectroscopic measurements. Legon, A. C.; Millen, D. J. Acc. Chem. Res. 1987, 20, 39-46.)Hydrogen BondingWhat you may not know:“Strength” of H-bond depends on context.What if molecules are dissolved in solvent that can also H-bond (like H2O)?Competitive H-bond interactions can make H-bond “worth” much less.Williams, D. H. et al. J. Chem. Soc. Chem. Commun. 1994, 1519.In water, how much is each hydrogen bond between receptor & ligand worth?Answer by successively removing H bonds.Hydrogen BondingWilliams, D. H. et al. J. Chem. Soc. Chem. Commun. 1994, 1519.remove 1 H-bond:ΔΔHa= +1.5 kcal/mol(association of ligand to pocket is 1.5 kcal/mol less favorable)remove another H-bond:ΔΔHa= +1.5 kcal/molWhy were H-bonds so much “weaker”in water than in the gas phase?Hydrogen BondingWilliams, D. H. J. Chem. Soc. Chem. Commun. 1994, 1519.remove 1 H-bond:ΔΔHd= +1.5 kcal/molremove another H-bond:ΔΔHd= +1.5 kcal/molWhy were H-bonds so much “weaker”in water than in the gas phase?Because H-bonded water recovers much of energy from broken H-bond.HOHHOHHOHHydrogen BondingH-bonds to solvent can prevail over H-bonds within a molecule.R N N N NOHHHOHHHOHHHOORHHHOCHCl3Gellman, S. H. et al. Chem. Rev. 2001, 101, 3219.Hydrogen BondingH-bonds to solvent can prevail over H-bonds within a molecule.R N N N NOHHHOHHHOHHHOORHHHOCHCl3DMSOGellman, S. H. et al. Chem. Rev. 2001, 101, 3219.Hydrophobic EffectZhou, R. et al. Science 2004, 305, 1605.If H-bonding solvents (like H2O) are so good at competing for H-bonds, how do biomolecules stay folded?The “hydrophobic effect”: more accurately de-solvation than a weak interaction.split enzymein half,BphC enzyme;hydrophilic residues (K,D,E,R,Q,N) redhydrophobic residues (I,F,V,M,W,C,Y) blue• Exclusion of hydrophobic residues from water important to folding;• H-bonds “stronger” inside the protein as a result.look atexposed facesDiscussion QuestionBases in DNA (“R” is DNA strand):NNOOH3CRHNNNNONRHHHNNNNNRHHNNNO RHHAssume that you can translate these bases however you want, but you can’t rotate them. How can they be paired? (There are more than two possible pairs!)If ΔGH-bond= 1.2 kcal/mol, how much are these pairs worth?Sartorius, J.; Schneider, H.-J. Chem. Eur. J. 1996, 2, 1446.Weak Arene InteractionsXHHHHHHHHHHHHHFFFFFFHHHHHHHHHHHHHHHHHH+arene-cation arene-H arene-areneET complexarene-arene• Aromatic face can act as electron donor• Forms interactions with dissociatonenergies ~ 1-5 kcal/molReview: Diederich, F. et al. Angew. Chem. Int. Ed. 2003, 42, 1210.Weak Arene InteractionsReview: Diederich, F. et al. Angew. Chem. Int. Ed. 2003, 42, 1210.How do we know?Experimental studies…+0.7-0.8-1.5benzene-0.8-3.1-2.3chloroform-0.3-3.0-2.7tetrahydrofuran-0.8-3.7-2.9N,N-dimethylformamide-2.5-6.4-3.9dimethyl sulfoxide-2.3-6.6-4.3acetone-4.9-11.0-6.1ethanol-5.6-12.0-6.4methanol-12.2-20.0-7.82,2,2-trifluoroethanol---9.4WaterTΔSa(kcal/mol)ΔHa(kcal/mol)ΔGa(kcal/mol)solvent…and crystallographic databases.Four examples of arene-(NR4+) boxes from Protein Data Bank searching(Shärer, K. et al. Angew. Chem. Int. Ed. 2005, 44, 4400.)Arene Donor InteractionsXHHHHHHHHHHHHHFFFFFFHHHHHH+Review: Diederich, F. et al. Angew. Chem. Int. Ed. 2003, 42, 1210.From nicotine receptor of acetylcholineesterase.Cationic ligands (like nicotine) bind aromatic Trp residuesArene-Arene InteractionsCrystal structure of benzene: Rings organized in herringbone structure (not stacked!)(MPOC p.184)Arene-Arene InteractionsExample: DNA(MPOC p.184)(From http://www.bio.cmu.edu/Courses/BiochemMols/Stacks/bpStacks.htm.Requires MDL Chime, at